Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith–Wiedemann syndrome

Abstract

Genomic imprinting is an epigenetic phenomenon restricting gene expression in a manner dependent on parent of origin. Imprinted gene products are critical regulators of growth and development, and imprinting disorders are associated with both genetic and epigenetic mutations, including disruption of DNA methylation within the imprinting control regions (ICRs) of these genes. It was recently reported that some patients with imprinting disorders have a more generalised imprinting defect, with hypomethylation at a range of maternally methylated ICRs. We report a cohort of 149 patients with a clinical diagnosis of Beckwith -Wiedemann syndrome (BWS), including 81 with maternal hypomethylation of the KCNQ1OT1 ICR. Methylation analysis of 11 ICRs in these patients showed that hypomethylation affecting multiple imprinted loci was restricted to 17 patients with hypomethylation of the KCNQ1OT1 ICR, and involved only maternally methylated loci. Both partial and complete hypomethylation was demonstrated in these cases, suggesting a possible postzygotic origin of a mosaic imprinting error. Some ICRs, including the PLAGL1 and GNAS/NESPAS ICRs implicated in the aetiology of transient neonatal diabetes and pseudohypoparathyroidism type 1b, respectively, were more frequently affected than others. Although we did not find any evidence for mutation of the candidate gene DNMT3L, these results support the hypotheses that trans-acting factors affect the somatic maintenance of imprinting at multiple maternally

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

“…Nevertheless, it is intriguing that a number of clinical features appeared to be more frequent in patients with MLID (Figure 4), such as facial nevus flammeus (5/6 MLID vs. 3/10 non-MLID), and, in contrast with previous reports [7], macroglossia (6/6 MLID vs. 6/10 non-MLID) and outer ears anomalies (3/6 MLID vs. 1/10 non-MLID). Also, abdominal wall defects were more frequent in both pre- and postnatal BWS-MLID patients (8/10 MLID vs. 4/11 non-MLID).…”

“…This hypothesis is also supported by the following evidences: i) both BWS epimutations (ICR1 GOM or ICR2 LOM) result from defective methylation of the maternal allele, and ii) no [7,19], or very few [15] cases with MLID have been identified among ICR1 hypermethylated patients.…”

“…This phenomenon, known as multiple maternal hypomethylation syndrome, has previously been described for BWS [7,16,17]. Only two studies reported on MLID as GOM at paternally methylated iDMRs in BWS patients [8,15]; however, also in these cases, MLID was supposed to arise as a consequence of a methylation defect of the maternal allele.…”

“…Methylation profile of 12 iDMRs frequently involved in MLID in BWS/SRS [7,8,10,15] was investigated by the MassARRAY methylation platform (Agena Bioscience, Hamburg, Germany). Details on the setting up and on protocol are reported in Supplementary materials and methods.…”

“…However, some exceptions have been reported. Specifically, birth weight is usually lower in patients with MLID than in those with mono-locus BWS, and macrosomia is less frequent; patients with MLID can present features not related to BWS (speech retardation, apnea, and feeding difficulties) [7]. SRS patients with MLID more frequently exhibit growth delay and additional congenital abnormalities [6].…”